| Literature DB >> 27368101 |
Kimberly J Briggs1, Peppi Koivunen2, Shugeng Cao3, Keriann M Backus4, Benjamin A Olenchock5, Hetalben Patel6, Qing Zhang7, Sabina Signoretti8, Gary J Gerfen6, Andrea L Richardson8, Agnieszka K Witkiewicz9, Benjamin F Cravatt4, Jon Clardy3, William G Kaelin10.
Abstract
The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIFα subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1α in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion. EglN1, the main HIFα prolyl-hydroxylase, undergoes oxidative self-inactivation in the absence of cysteine both in biochemical assays and in cells, resulting in HIF1α accumulation. Therefore, EglN1 senses both oxygen and cysteine.Entities:
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Year: 2016 PMID： 27368101 PMCID： PMC4930557 DOI： 10.1016/j.cell.2016.05.042
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582